Schistosomiasis is a serious, potentially fatal parasitic disease afflicting about 200 million people primarily in Africa, South America and some parts of the Middle East and Asia. The basic pathology in schistosomiasis is a CD4 T cell-mediated granulomatous inflammatory reaction against parasite eggs, which in the case of infection with Schistosoma mansoni, primarily takes place in the liver and intestines. Both in humans, as well as in a murine model, there is marked heterogeneity in the severity of disease. However, the precise regulatory mechanisms that dictate the extent of immunopathology are poorly understood. The main objective of this proposal is to investigate the role of dendritic cells (DC) in determining disease severity in murine schistosomiasis. The specific goals of this project are 1) to determine if DC isolated from high but not low pathology mouse strains can be stimulated to become activated and produce pro- inflammatory cytokines following exposure to live schistosome worms and eggs and 2) to determine if high versus low pathology DC exposed to schistosome products preferentially drive the differentiation of CD4 T cell populations to become pathogenic Th17 or protective Th2 cells, respectively. Among several standard state of the art techniques, this project will take advantage of a novel, unique S. manson/-specific TCR transgenic mouse system. Since DC are a critical link between innate and adaptive immunity, this project will provide invaluable insight into how immunopathology develops from the initial invasion of the parasite to the pathogenic T cell-mediated formation of granulomatous lesions. Despite a highly effective drug treatment with praziquantel, re-infection with schistosomes is a common occurrence in the endemic regions of the world. Unfortunately, a vaccine for schistosomiasis has yet to be developed. The research proposed in this grant will contribute to the understanding of the basic pathogenesis of schistosomiasis and to the design of specific immunotherapies.